Neoadjuvant Radiochemotherapy Alters the Immune and Metabolic Microenvironment in Oral Cancer—Analyses of CD68, CD163, TGF-β1, GLUT-1 and HIF-1α Expressions
Background: The first-line treatment of oral squamous cell carcinoma (OSCC) involves surgical tumor resection, followed by adjuvant radio(chemo)therapy (R(C)T) in advanced cases. Neoadjuvant radio- and/or chemotherapy has failed to show improved survival in OSCC. Recently, neoadjuvant immunotherapy...
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MDPI AG
2024-02-01
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| Online Access: | https://www.mdpi.com/2073-4409/13/5/397 |
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| author | Manuel Weber Jutta Ries Kristina Braun Falk Wehrhan Luitpold Distel Carol Geppert Rainer Lutz Marco Kesting Leah Trumet |
| author_facet | Manuel Weber Jutta Ries Kristina Braun Falk Wehrhan Luitpold Distel Carol Geppert Rainer Lutz Marco Kesting Leah Trumet |
| author_sort | Manuel Weber |
| collection | DOAJ |
| description | Background: The first-line treatment of oral squamous cell carcinoma (OSCC) involves surgical tumor resection, followed by adjuvant radio(chemo)therapy (R(C)T) in advanced cases. Neoadjuvant radio- and/or chemotherapy has failed to show improved survival in OSCC. Recently, neoadjuvant immunotherapy has shown promising therapeutic efficacy in phase 2 trials. In this context, the addition of radio- and chemotherapy is being reconsidered. Therefore, a better understanding of the tumor-biologic effects of neoadjuvant RCT would be beneficial. The current study was conducted on a retrospective cohort of patients who received neoadjuvant RCT for the treatment of oral cancer. The aim of the study was to evaluate the influence of neoadjuvant RCT on the immunological tumor microenvironment (TME) and hypoxic and glucose metabolisms. Methods: A cohort of 45 OSSC tissue samples from patients were analyzed before and after RCT (total 50.4 Gy; 1.8 Gy 5× weekly; Cisplatin + 5-Fluorouracil). Immunohistochemistry for CD68, CD163, TGF-β, GLUT-1 and HIF-1α was performed using tissue microarrays and automated cell counting. Differences in expression before and after RCT and associations with histomorphological parameters (T-status, N-status) were assessed using the Mann–Whitney U test. Results: Tumor resection specimens after neoadjuvant RCT showed a significant decrease in CD68 infiltration and a significant increase in CD163 cell density. The CD68/CD163 ratio was significantly lower after RCT, indicating a shift toward M2 polarization. The GLUT-1 and HIF-1α expressions were significantly lower after RCT. Larger tumors (T3/T4) showed a lower GLUT-1 expression. Other biomarkers were not associated with the T- and N-status. Conclusions: Neoadjuvant RCT with 50.4 Gy induced a shift toward the M2 polarization of macrophages in the TME. This change in immune composition is not favorable and may be prognostically negative and counteract immunotherapeutic approaches. In addition, the decreased expressions in GLUT-1 and HIF-1α indicate reductions in the glucose metabolism and hypoxic energy metabolism in response to “high dose” neoadjuvant RCT, which may be therapeutically desirable. |
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| language | English |
| last_indexed | 2024-04-25T00:33:02Z |
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| spelling | doaj.art-1cd78e519f4f41df9a69f5ba375c61da2024-03-12T16:41:34ZengMDPI AGCells2073-44092024-02-0113539710.3390/cells13050397Neoadjuvant Radiochemotherapy Alters the Immune and Metabolic Microenvironment in Oral Cancer—Analyses of CD68, CD163, TGF-β1, GLUT-1 and HIF-1α ExpressionsManuel Weber0Jutta Ries1Kristina Braun2Falk Wehrhan3Luitpold Distel4Carol Geppert5Rainer Lutz6Marco Kesting7Leah Trumet8Department of Oral and Cranio-Maxillofacial Surgery, Uniklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Glückstraße 11, 91054 Erlangen, GermanyDepartment of Oral and Cranio-Maxillofacial Surgery, Uniklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Glückstraße 11, 91054 Erlangen, GermanyDepartment of Oral and Cranio-Maxillofacial Surgery, Uniklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Glückstraße 11, 91054 Erlangen, GermanyDepartment of Oral and Cranio-Maxillofacial Surgery, Uniklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Glückstraße 11, 91054 Erlangen, GermanyDepartment of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, GermanyInstitute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, GermanyDepartment of Oral and Cranio-Maxillofacial Surgery, Uniklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Glückstraße 11, 91054 Erlangen, GermanyDepartment of Oral and Cranio-Maxillofacial Surgery, Uniklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Glückstraße 11, 91054 Erlangen, GermanyDepartment of Oral and Cranio-Maxillofacial Surgery, Uniklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Glückstraße 11, 91054 Erlangen, GermanyBackground: The first-line treatment of oral squamous cell carcinoma (OSCC) involves surgical tumor resection, followed by adjuvant radio(chemo)therapy (R(C)T) in advanced cases. Neoadjuvant radio- and/or chemotherapy has failed to show improved survival in OSCC. Recently, neoadjuvant immunotherapy has shown promising therapeutic efficacy in phase 2 trials. In this context, the addition of radio- and chemotherapy is being reconsidered. Therefore, a better understanding of the tumor-biologic effects of neoadjuvant RCT would be beneficial. The current study was conducted on a retrospective cohort of patients who received neoadjuvant RCT for the treatment of oral cancer. The aim of the study was to evaluate the influence of neoadjuvant RCT on the immunological tumor microenvironment (TME) and hypoxic and glucose metabolisms. Methods: A cohort of 45 OSSC tissue samples from patients were analyzed before and after RCT (total 50.4 Gy; 1.8 Gy 5× weekly; Cisplatin + 5-Fluorouracil). Immunohistochemistry for CD68, CD163, TGF-β, GLUT-1 and HIF-1α was performed using tissue microarrays and automated cell counting. Differences in expression before and after RCT and associations with histomorphological parameters (T-status, N-status) were assessed using the Mann–Whitney U test. Results: Tumor resection specimens after neoadjuvant RCT showed a significant decrease in CD68 infiltration and a significant increase in CD163 cell density. The CD68/CD163 ratio was significantly lower after RCT, indicating a shift toward M2 polarization. The GLUT-1 and HIF-1α expressions were significantly lower after RCT. Larger tumors (T3/T4) showed a lower GLUT-1 expression. Other biomarkers were not associated with the T- and N-status. Conclusions: Neoadjuvant RCT with 50.4 Gy induced a shift toward the M2 polarization of macrophages in the TME. This change in immune composition is not favorable and may be prognostically negative and counteract immunotherapeutic approaches. In addition, the decreased expressions in GLUT-1 and HIF-1α indicate reductions in the glucose metabolism and hypoxic energy metabolism in response to “high dose” neoadjuvant RCT, which may be therapeutically desirable.https://www.mdpi.com/2073-4409/13/5/397macrophage polarizationimmune tolerancehypoxiametabolisminduction therapyRCT |
| spellingShingle | Manuel Weber Jutta Ries Kristina Braun Falk Wehrhan Luitpold Distel Carol Geppert Rainer Lutz Marco Kesting Leah Trumet Neoadjuvant Radiochemotherapy Alters the Immune and Metabolic Microenvironment in Oral Cancer—Analyses of CD68, CD163, TGF-β1, GLUT-1 and HIF-1α Expressions Cells macrophage polarization immune tolerance hypoxia metabolism induction therapy RCT |
| title | Neoadjuvant Radiochemotherapy Alters the Immune and Metabolic Microenvironment in Oral Cancer—Analyses of CD68, CD163, TGF-β1, GLUT-1 and HIF-1α Expressions |
| title_full | Neoadjuvant Radiochemotherapy Alters the Immune and Metabolic Microenvironment in Oral Cancer—Analyses of CD68, CD163, TGF-β1, GLUT-1 and HIF-1α Expressions |
| title_fullStr | Neoadjuvant Radiochemotherapy Alters the Immune and Metabolic Microenvironment in Oral Cancer—Analyses of CD68, CD163, TGF-β1, GLUT-1 and HIF-1α Expressions |
| title_full_unstemmed | Neoadjuvant Radiochemotherapy Alters the Immune and Metabolic Microenvironment in Oral Cancer—Analyses of CD68, CD163, TGF-β1, GLUT-1 and HIF-1α Expressions |
| title_short | Neoadjuvant Radiochemotherapy Alters the Immune and Metabolic Microenvironment in Oral Cancer—Analyses of CD68, CD163, TGF-β1, GLUT-1 and HIF-1α Expressions |
| title_sort | neoadjuvant radiochemotherapy alters the immune and metabolic microenvironment in oral cancer analyses of cd68 cd163 tgf β1 glut 1 and hif 1α expressions |
| topic | macrophage polarization immune tolerance hypoxia metabolism induction therapy RCT |
| url | https://www.mdpi.com/2073-4409/13/5/397 |
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